Project Summary/Abstract Maternal infection and fever increase susceptibility of offspring to several brain disorders including autism (ASD), schizophrenia (SZ), and major depression (MDD). Animal models of maternal immune activation (MIA) support this link, as mid-gestational injection of the viral mimic, poly(I:C), induces a wide range of disease- related behavioral and neuropathological abnormalities in adult offspring. Yet, current approaches using this model ignore two of the most important aspects of human psychiatric illness: (i) most pregnancies are resilient to maternal viral infection and (ii) susceptible pregnancies can lead to multiple neurodevelopmental and psychiatric disorders in offspring. Our laboratory has recently discovered a way to study both of these issues in the MIA mouse model. We have recently found that virgin female C57/B6 mice exhibit a wide range of baseline immunoreactivity (BIR) that dictates susceptibility or resilience of subsequent pregnancies to MIA-induced, disease-related outcomes in offspring. Surprisingly, intermediate (but not low and high) poly(I:C) doses are selectively effective at increasing repetitive behaviors in adult male offspring and offspring exposed to the same intermediate dose during gestation exhibit distinct subsets of abnormal behaviors that are reproducibly predicted by the BIR of the dam. These results have revealed, for the first time, a factor (BIR) that confers resilience as well susceptibility to specific combinations of endophenotypes in MIA offspring. The central goals of my project are to identify the striatal connectivity changes in offspring and the role of interleukin-6 (IL-6) signaling in the dam that confer resilience or susceptibility to specific combinations of MIA-induced behavioral outcomes. In Aim 1, I will determine if the magnitude of MIA predicts resilience and susceptibility of offspring to behavioral deficits, and whether susceptible individuals show distinct, BIR-driven behavioral signatures. In Aim 2, I will determine whether MIA results in distinct connectivity changes in afferent neurons, dopaminergic circuits, synapse density and balance of excitatory and inhibitory synapses in striatum using array tomography and retrograde viral tracing. Finally, in Aim 3, I will employ a combination of experiments utilizing IL-6 supplementation and inhibition to reveal whether IL-6 alone is necessary and sufficient to dictate susceptibility and resilience to alterations in striatal dependent behaviors and circuitry. Most important, I will determine if manipulation of IL-6 levels can convert susceptible pregnancies into resilient ones. If successful, my project may identify biomarkers to predict pregnancies most at risk and approaches to prevent offspring from developing psychiatric disorders.